We have identified a novel neuropeptide, termed NPS, that is predominantly expressed in a cluster of previously unidentified neurons in close vicinity to the noradrenergic locus coeruleus. The locus coeruleus is a brainstem structure involved in regulating sleep-wake cycles, arousal, attention and stress. Dysfunction of this brain area has been implicated in a number of disorders such as insomnia, narcolepsy and attention deficit hyperactivity disorder. More widespread expression of the NPS receptor is found in several brain areas, including cortex, thalamus and hypothalamus. Our preliminary results show that NPS promotes arousal when injected in mice. NPS also induces wakefulness while suppressing REM sleep and deep sleep in rats. Furthermore, NPS appears to produce anxiolytic-like effects. Therefore, NPS could represent a new transmitter system involved in neuronal modulation of vigilance and stress. We propose to study in detail the anatomical distribution of this novel transmitter system and the pharmacology of its receptor. We will determine the coexistence of NPS with known transmitters and its effect on the release of other transmitters involved in arousal. Furthermore, we will investigate its role in sleep and wakefulness and a possible involvement in attention and anxiety. Since no antagonist to the NPS receptor is currently available, we propose a genetic approach to delete the NPS gene in mice and study the behavioral consequences of NPS deficiency. Together, these studies will lay the foundation for understanding the physiological functions of NPS which may also yield new insights into human psychiatric disorders. A mutation in the human NPS receptor was recently found to be associated with increased risk of asthma. We will study the pharmacology of the mutant receptor isoforms which may help to understand the physiological consequences of the mutation in human airway tissue.